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I'm working on a 15" x 21" poster than folds into a 5" x 7" card for mailing. The poster will be folded open, but the content will not necessarily be neatly contained in each 5" x 7" section — some content takes over two panels, some all three).

What is a best practice for creating a grid for such a poster?

Currently my grid divides each 5" x 7" section, with gutters that allow for room across each fold. While this ensures that small type near the fold will not cross it, the poster contains content that spans multiple columns and sections. This results in an uneven spacing of said columns (six columns appear more like three columns on one section followed by a large gutter and three more columns in another section).

I can't have it both ways — either the typographic grid will align with the folding grid, causing some gutter issues, or the typographic grid will not align with the folding grid. What's the best way?

Using rag right columns (rather than justified) may help make the uneven column spacing less obvious.

For articles that span folds, perhaps a graphic element could be used to visually group together the related text. For example, put a tinted background behind the article's columns, or put them in a box, or have a rule span those columns, or group those columns via text style or color.

I had read the Vignelli cannon before, but confess I had forgotten about it. A re-reading had me re-consider my complex grid and come up with something more simple. I used 1 pica margins for the left and right, and 2 pica column gutters. Using James' advice on running rag right text, the large gutters seem less imposing, especially with a minimum type size of 8pt.